Aripiprazole - Abilify

[Jaybee00]

Most/many people with MECFS respond positively to steroids—we’ve already discussed this and you said you weren’t sure about the mechanism.

I have been trying to think of something useful to add to the debate here. I am not sure I know enough answers though. Prednisolone has often been used as a way of testing to see if an illness is inflammatory - as judged by an immediate response. However, it also produces a high for a lot of people regardless of inflammation.

The other point is that symptoms in ME may be due to signals that often go with inflammation but are not actually part of inflammation per se. As an example, injection of a bacterial extract like typhoid vaccine will produce the malaise that usually goes with inflammation without there being any actual inflammation. The toxins have a direct effect on the hypothalamus without any tissues actually being inflamed.

The fact that a number of people with ME seem to get relief from steroids does suggest to me that these sorts of signals are involved but it may not be true for all. Nevertheless, in the long term steroids tend to have more risks than benefits and very often the beneficial effect wears off.

 

[benji]

I am trying Abilify now, I started last week on 0,25mg/day and have increased to 0,5mg.
I am certainly feeling better, but I haven’t started to increase activity much yet. Just enjoying feeling better/having better cognitive function.
The last improvement I had was last year with the ketogenic diet, and the improvement only lasted some months. And it was fabulous, I felt very light, like I ruled the world and could do anything. This improvement is not like that, but is still very good. And maybe.. I won’t crash in some months of it.

 

[leokitten]

I am trying Abilify now, I started last week on 0,25mg/day and have increased to 0,5mg.
I am certainly feeling better, but I haven’t started to increase activity much yet. Just enjoying feeling better/having better cognitive function.
The last improvement I had was last year with the ketogenic diet, and the improvement only lasted some months. And it was fabulous, I felt very light, like I ruled the world and could do anything. This improvement is not like that, but is still very good. And maybe.. I won’t crash in some months of it.

You could’ve written this about me too. I had same the experience as you @benji.

I’m also trialing Abilify 0.5 mg and have had a really significant improvement on it. I’ve been bedridden 22-23 hours a day for 5 months and was housebound before that all of 2020 only able to go outside once every 2-3 weeks. Now I’m out of bed and able to function much better instead of in a crash or just staring at the ceiling in ME zombie hell most of the day.

Abilify is way different to me than how keto felt and improved my symptoms. At least at 0.5 mg it’s not stimulating at all or pushing me to exert in any way. I just feel way better across all my ME symptoms. I don’t get PEM now though I also haven’t exerted a lot more except to do one experiment to prove to myself it’s not placebo effect by doing something that would certainly cause a crash before. No crash no PEM.

Also I have no discernible side effects.

 

[Trish]

I’m also trialing Abilify 0.5 mg and have had a really significant improvement on it.

That's nice to hear. I hope the improvements continue for you. Are you just taking abilify at the moment or are you on other treatments too?

 

[benji]

That’s great to hear @leokitten. I haven’t got any side effects either. But I still have PEM.
I am going to try more doses. I am in this FB group “Abilify for ME/cfs”
Anyway it is great not to be in bed as a much as I was before, I was also at 22-23 hours per day. Before keto, and before Abilify.
We really need some relief with this disease.

 

[leokitten]

That's nice to hear. I hope the improvements continue for you. Are you just taking abilify at the moment or are you on other treatments too?

I’m taking moclobemide (RIMA MAOI) at the lowest therapeutic dose of 300 mg/day. I’d been taking moclobemide for over 2 months by itself before and had no significant improvement other than some very minor improvement in mental energy only when lying in bed. If I started getting up and exerting it didn’t provide any benefit.

I’m taking LDN 4.5 mg/day. I took LDN a few years ago for about a year and it did absolutely nothing.

I’m taking etoricoxib (Arcoxia) 30 mg/day. I took etoricoxib 60 mg/day last year for a few months on its own and it also felt like it did nothing.

I decide to take these with Abilify because of anecdotal reports of possible synergistic effect and because none of these other meds gave me any side effects.

It took almost 2 1/2 weeks into Abilify until I felt the effects start creeping up day by day. At 0.25 mg I felt nothing and was at that dose for almost 2 weeks. I raised the dose to 0.5 mg and after a couple days things started to change. Abilify accumulates for about 2 weeks until it reaches steady state so maybe 0.25 would’ve been enough who knows.

I’m not taking any supplements and every few days take sleep medication which I’ve been taking for years during ME.

After reading the Stanford paper my expectation was that this drug wasn’t going to work very well and be more or less of a disappointment like almost everything else I’ve tried. But I was completely wrong, what other people have been saying about it’s effect on them I totally understand now.

I want to be clear I still very much feel that I have ME. I don’t feel like before ME. But it reduces my symptoms substantially. Symptoms feel much more manageable, less debilitating, and I have increased my exertion to be able to stay out of bed all day without getting any PEM. I’m not exerting a huge amount but am able to do substantially more physical and mental exertion than before even though I’m holding back and taking it easy.

I just find it frankly impossible that this could be placebo effect. I did an experiment on Monday where I physically and mentally exerted enough to guarantee a huge crash before Abilify. It’s Thursday and no PEM no crash. I won’t do it again but had to prove it to myself.

It also doesn’t feel at all like “fake” energy. Ketogenic felt like that. Abilify just feels like my symptoms all took a major step in the direction towards normal, particularly PEM. That’s the best way I can describe it.

 

[leokitten]

I am trying Abilify now, I started last week on 0,25mg/day and have increased to 0,5mg.

Your time to response (7-10 days) is more typical from what I read. People report that benefits continue to increase for a while after that until stabilizing.

Did it make you feel worse and irritable the first week before everything turned around? A lot of people reported that but I didn’t get that at all. Didn’t feel anything for a while.

 

[Wits_End]

At least at 0.5 mg it’s not stimulating at all

Are you positive about that?

I have increased my exertion to be able to stay out of bed all day without getting any PEM. I’m not exerting a huge amount but am able to do substantially more physical and mental exertion than before even though I’m holding back and taking it easy.

I'd have thought even that could be regarded as "stimulating".

I’m taking moclobemide (RIMA MAOI) at the lowest therapeutic dose of 300 mg/day.

Sounds as though you're using Abilify to augment the moclobemide, then?

I think my caree has probably come off it. I must ask her.

 

[leokitten]

Are you positive about that?

Yes, it doesn’t feel stimulating at all. Symptoms have reduced and I just feel better. But I’m not restless, mind not racing, not feeling pushed to move around or do things.

I'd have thought even that could be regarded as "stimulating".

Well I was bedridden lying down or sleeping all but 1-2 hours a day where I could sit up or sometimes make it to the living room. That’s very little exertion so almost anything sounds like a lot more than that.

I can get out of bed now every morning and go to the living room, I can read and watch TV more, I can socialize a bit more, I can prepare food a bit more instead of not eating or only being able to eat things without any preparation, and I can self-care more than every couple weeks. It’s still not a lot of exertion in absolute terms, just relative to being bedridden it seems like a big difference.

I think you likely know this, but no one wants to stay stuck in bed all day and night, day after day, if they feel well enough to get out of it. It’s not a stimulating drug feeling it’s a basic drive to not be in that horrible state.

Sounds as though you're using Abilify to augment the moclobemide, then?

Moclobemide didn’t do much wrt ME on its own, and I took it more than long enough for it to have an effect. The Abilify antidepressant augmentation dose is 5–10 mg, so 10x more than I’m taking. I was speculating that they would synergistically work better together and decided to keep taking it with Abilify. Moclobemide also has evidence of being an anti-inflammatory.

 

[Snow Leopard]

Most/many people with MECFS respond positively to steroids—we’ve already discussed this and you said you weren’t sure about the mechanism.

Yes, there were three double blinded RCT published in The Lancet, JAMA etc with positive results. The lack of a generalised recommendation was due to risk of side effects.

 

[Jonathan Edwards]

Most/many people with MECFS respond positively to steroids—we’ve already discussed this and you said you weren’t sure about the mechanism.

As I said before I am not sure I have much more to add, but the situation is complicated.

Steroids give people a high so the fact that trials show some symptomatic improvement in the short term does not tell us much.

Steroids block all sorts of signals and as I said before I think it is possible that some ME/CFS cases are dependent on some of these signals although not ones that lead to overt inflammation.

The suggestion was that blocking something like Syk kinase might be relevant. My thought was that if Syk was activated we would expect at least some sign of inflammatory signals involving the kinase pathways that lead to for instance TNF or IL-1 production.

This might perhaps not necessarily be true. However, the other point about steroids is that although they have a poor benefit/adverse event profile they are actually better than almost anything else that is designed to block intracellular signals like kinases. We can block intercellular signals like cytokines (TNF, IL-1) very specifically without adverse effects but kinase inhibitors have been very one to adverse effects even after thirty years of trying to find specific and safe agents. In RA a jak kinase inhibitor has been licensed since I retired I think but syk kinase inhibitors have not come through as far as I know. Most agents that do something to these kinases produce a mass of unwanted effects including CNS effects. If people have got nowhere with multimillion dollar programmes deliberately targeting these molecules it seems unlikely that a drug designed to do something different that has a smidgin of effect on a kinase would do better.

 

[Hubris]

Anecdotal of course but i tried very high dose steroids for 10 days (methylprednisolone 160mg per day) and they only made many of my symptoms worse (mainly disautonomia related). 0 improvement.

 

[leokitten]

If people have got nowhere with multimillion dollar programmes deliberately targeting these molecules it seems unlikely that a drug designed to do something different that has a smidgin of effect on a kinase would do better.

I personally take from the referenced paper that this is some additional evidence documenting Abilify’s potential anti-inflammatory molecular mechanisms in the CNS, not necessarily finding new drug targets. There is still so much to learn about the mechanisms of action of dopamine-serotonin stabilizers (DSS) like Abilify.

 

[leokitten]

For those of you who also read PR, we’ve also discussed potential alternative DSS drugs and add-ons there as there are many people who responded very positively to Abilify but after ~4 months or so it stops working.

In fact, I’d searched a little while back and found there are testimonials on PR going back even to 2012 on Abilify, and also testimonials of people experiencing the same loss of efficacy at ~4 months and how they worked around it.

Regarding similar therapies, I’m particularly interested in brilaroxazine (RP5063). It’s starting phase III trials (for schizophrenia) this year after successful phase I and II trials. They are also undergoing trials for other indications like depression, PAH, and IPF.

With a seemingly small change to the aripiprazole molecule, brilaroxazine (or oxaripiprazole) doesn’t appear to have almost any off-target receptor effects and most importantly seems to have no metabolic side effects.

 

[leokitten]

https://en.m.wikipedia.org/wiki/Brilaroxazine

It’s almost identical molecular structure to aripiprazole, with only a single carbon change in the quinolinone ring system to oxygen making it a benzoxazinone ring system. The resulting change also makes it closely related to cariprazine.

Brilaroxazine (RP5063) Clinical Experience in Schizophrenia: "A New Option to Address Unmet Needs"

Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder. Cantillon et al. Schizophr Res (2017)

RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia. Rajagopal et al. Behav Brain Res (2017)

Brilaroxazine (RP5063) seems to have fewer potential side effects compared to aripiprazole (which itself already had fewer side effects than other antipsychotics).

It doesn’t seem to cause any metabolic side effects compared to placebo and other antipsychotics, which is a big improvement compared to even aripiprazole. Patient’s glucose, lipids, and prolactin all actually decreased, and there were no significant changes in weight.

I think Ron Davis was looking for an alternative dopamine-serotonin stabilizer drug with a similar mechanism of action and binding profile to aripiprazole but doesn’t have the negative metabolic side effects, well brilaroxazine seems to be a good candidate.

They’ve already completed phase 1 and phase 2 trials for schizophrenia and are preparing phase 3 (https://revivapharma.com/clinical-trails/).

 

[leokitten]

A good summary document on brilaroxazine from an investment research firm looking at Reviva.

https://s1.q4cdn.com/460208960/files/News/2021/Zacks_SCR_Research_01132021_RVPH_Vandermosten.pdf

You can see the important improvements compared to aripiprazole, eg target receptor binding and affinities, virtually non existent off-target binding, much improved side effect profile (see bar charts summarizing results from phase II trial and comparing to aripiprazole 15 mg).

There’s also a decent summary table comparing all the existing antipsychotics at target receptors.

They are starting phase III trials (for schizophrenia) this year and looks like if everything is successful will be FDA approved in 2025. They are also in earlier trials stages for other indications and looks like it has potential for quite a number of indications.

 

[benji]

Did it make you feel worse and irritable the first week before everything turned around? A lot of people reported that but I didn’t get that at all. Didn’t feel anything for a while.

No I didn’t. I felt better almost from the first day, on my mood. One has to have energy to keep the spirit up, and lately I haven’t had that. But that changed almost day 1. Though, I think I am better now than then. I keep trying how the body works now, and today has been a very good day, the best day so far. I guess the best is to have the lowest dose that works, both for economy and eventually tolerance in the future, so I may stay at 0,5mg a while after all.
I know it takes time to reach steady state due to long half-life, and since I am not very sensitive to medication I do “loading dose” to reach steady state sooner.

I haven’t read many other stories, maybe I will look up ton PR. But in the FB group the vast majority report than they felt improving within the first week. (A poll).

 

[leokitten]

Currently to me these are the hypotheses for Abilify efficacy in ME:

1. Positively affects neurotransmitter or signaling dysfunction via dopamine-serotonin system stabilization and functional selectivity
2. CNS anti-inflammatory
3. Positively affects cellular metabolism dysfunction
4. Positively affects hypothalamus and pituitary gland dysfunction

As you can tell these hypotheses are overlapping and it could be all of these.

I’ve been reading papers to look more closely at 3 and 4 but it’s been slow going as takes a lot of background reading. Aripiprazole affects cellular metabolism and energy sensing as well as endocrine function. Antipsychotics all do but they have really different effects depending on the drug.

 

[dreampop]

Currently to me these are the hypotheses for Abilify efficacy in ME:

1. Positively affects neurotransmitter or signaling dysfunction via dopamine-serotonin system stabilization and functional selectivity
2. CNS anti-inflammatory
3. Positively affects cellular metabolism dysfunction
4. Positively affects hypothalamus and pituitary gland dysfunction

As you can tell these hypotheses are overlapping and it could be all of these.

I’ve been reading papers to look more closely at 3 and 4 but it’s been slow going as takes a lot of background reading. Aripiprazole affects cellular metabolism and energy sensing as well as endocrine function. Antipsychotics all do but they have really different effects depending on the drug.

Are you concerned at all about what will happen when Abilify no longer provides benefits, be that 4 months from when you started or some other date? Or are you happy to just take what you can for now?

 

[benji]

Are you concerned at all about what will happen when Abilify no longer provides benefits, be that 4 months from when you started or some other date? Or are you happy to just take what you can for now?

I think one has to do both, be happy for what is now, and also be aware of that it may not last forever. Before KD I also had improvement of Rituximab that didn’t last. The first time, you think you have a new life. The third time, I am not telling anyone, one learns to be catious. I don’t think I have heard anyone being worse than the starting point in Abilify. Maybe one, in the FB group. But most don’t.